Reduction in Lipoprotein (a) With the PCSK9 Monoclonal Antibody Evolocumab (AMG 145): A Pooled Analysis of Over 1300 Patients in 4 Phase 2 Trials

Study Questions:

What is the effect of PCSK9 inhibition on circulating levels of lipoprotein (a) [Lp(a)]?


This was a pooled analysis of data from 1,359 patients in four phase 2 trials to assess the effects of evolocumab, a human monoclonal antibody to PCSK9, on Lp(a) levels.


Evolocumab treatment for 12 weeks resulted in significant (p < 0.001) dose-related reductions in Lp(a) compared to control; 29.5% and 24.5% with 140 mg and 420 mg dosed every 2 and 4 weeks, respectively, with no plateau of effect. Lp(a) reductions were significantly correlated with reductions in low-density lipoprotein (LDL) cholesterol (correlation coefficient 0.5134, p < 0.001) and apoB (correlation coefficient 0.5203, p < 0. 001). Mean percentage reductions did not differ based on age or gender, but trended greater in those on statins.


The authors concluded that inhibition of PCSK9 with evolocumab results in dose-related reductions in Lp(a).


Lp(a) is an LDL-like particle consisting of apoB bound to apoliprotein (a). Because apolipoprotein (a) contains kringle repeats similar to plasminogen and may interfere with plasmin activity, the Lp(a) particle may be both proatherogenic and prothrombotic. Although several studies support a causal role between Lp(a) levels and vascular events, lowering Lp(a) through dietary or pharmacologic interventions has been difficult. The current data confirm the effects of PCSK9 inhibitors towards significant and sustained reductions of Lp(a). Since clearance of Lp(a) does not appear to be LDL receptor dependent, the mechanism by which PCSK9 inhibition lowers Lp(a) remains unclear.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: Lipoproteins, LDL, Kringles, Cholesterol, LDL, Fibrinolysin, Receptors, LDL

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